While the prognosis of early stage head and neck squamous cell carcinoma is excellent with standard surgical and chemo-radiation treatment strategies, effective treatment modalities for advanced or recurrent disease are lacking. Various immunotherapy clinical trials failed to show therapeutic benefits for these patients, and immune evasion mechanisms and tolerance to the tumor have been implicated as reasons for poor immunotherapy results. In this light, toll like receptor 4 (TLR4) agonists have been shown to overcome host tolerance and enhance anti-tumor immune responses in murine cancer models. The scientific and clinical goals of this proposal are to evaluate the efficacy of TLR4 agonists formulated in combination with GM-CSF secreting tumor vaccines in preclinical models and to study their potential use as part of a combinatorial vaccine in head and neck squamous cell cancer patients. Specifically, this proposal will 1) evaluate the efficacy of TLR4 agonists in combination with GM-CSF secreting whole cell tumor vaccines in murine models, 2) conduct a phase I clinical trial to study the safety and feasibility of TLR4 agonist injections intratumorally, and 3) develop autologous head and neck cancer cell vaccine that can be co-formulated with TLR4 agonists. This proposal also serves to develop the candidate's specialization as an independent clinician-scientist who can conduct competitive patient-oriented research. The candidate is currently an Assistant Professor of Otolaryngology/Head &Neck Surgery at Johns Hopkins University. The research will be mentored by Dr. Drew Pardoll, a leader in the field of tumor immunology, who has a 20 year track record of mentoring junior faculty members and fellows to become independent investigators in the field of tumor immunology and translational immunotherapy. Furthermore, the research will take place at Sidney Kimmel Comprehensive Cancer Center, a rich clinical-scientific working environment for integrated laboratory and translational clinical research with critical infrastructures to facilitate novel translational investigations. The long term goal is to establish a tumor immunotherapeutic program that can bring TLR4 agonists combined with other immunotherapeutic treatments into clinical trials in advanced head and neck cancer patients. Moreover, beyond the specific treatment of head and neck cancer patients, this research can be applicable to other malignancies that are not amenable to conventional treatments.